Oleamide (1) is an endogenous fatty acid primary amide shown to accumulate in the cerebrospinal fluid under conditions of sleep deprivation and disappear upon sleep recovery (Cravatt et al. (1995) Science 268, 1506-1509; Lerner et al. (1994) Proc. Natl. Acad. Sci. USA 91, 9505-9508; Cravatt et al. (1996) J. Am. Chem. Soc. 118, 580-590). In a structurally specific manner, it has been shown to induce physiological sleep in animals when administered by ip or iv injection. Consistent with its role as a prototypical member of a new class of biological signaling molecules, enzymatic regulation of the endogenous concentrations of oleamide has been described or proposed.
Fatty acid amide hydrolase (FAAH, oleamide hydrolase) is an integral membrane protein that degrades 1 to oleic acid and potent inhibitors (Ki=13 .mu.M.sup.-1 nM) of the enzyme with sleep-inducing properties have been detailed. The purification, characterization, cloning, expression and neuronal distribution of FAAH have been disclosed and it was found to possess the capabilities of hydrolyzing a range of fatty acid amides including anandamide which serves as an endogenous ligand for cannabinoid receptors.
In contrast to anandamide, an appealing feature of the members of this new class of biological signaling agents is the primary amide suggesting that their storage and release may be controlled in a manner analogous to that of short peptide hormones and messengers terminating in a primary amide (Patterson et al. (1996) J. Am. Chem. Soc. 118, 5938-5945; Cravatt et al. (1996) Nature 384, 83-87; Giang et al. (1997) Proc. Natl. Acad. Sci. USA 94, 2238-2242; Merkler et al. (1996) Arch. Biochem. Biophys. 330, 430-434; Devane et al. (1992) Science 258, 1946-1949; Johnson et al. (1993) Protaglandins, Leukot. Essent. Fatty Acids 48, 429-437; Di Marzo et al. (1995) Prostaglandins, Leukot. Essent. Fatty Acids 53, 1-11).